Department of Gastroenterology, Kidney Disease and Hemodialysis Center, Shaanxi Provincial People's Hospital, Xi'an, China.
Kidney Disease and Hemodialysis Center, Shaanxi Provincial People's Hospital, Xi'an, China.
Endocrinol Metab (Seoul). 2022 Jun;37(3):432-443. doi: 10.3803/EnM.2021.1336. Epub 2022 May 16.
This study investigated the effect of short-chain fatty acids (SCFAs) on diabetes in a mouse model.
Autophagy in Akita mice and streptozocin (STZ)-induced diabetic C57BL/6 mice was determined by Western blots and immunohistochemistry (IHC). Western blots, IHC, hematoxylin and eosin staining, Masson staining, periodic acid-Schiff staining, and picrosirius red staining were conducted to detect whether autophagy and renal function improved in Akita mice and STZ-induced diabetic C57BL/6 mice after treatment of SCFAs. Western blots, IHC, and chromatin immunoprecipitation were performed to determine whether SCFAs affected diabetic mice via the histone deacetylase (HDAC2)/unc-51 like autophagy activating kinase 1 (ULK1) axis. Diabetic mice with kidney-specific knockout of HDAC2 were constructed, and IHC, Masson staining, and Western blots were carried out to detect whether the deletion of endogenous HDAC2 contributed to the improvement of autophagy and renal fibrosis in diabetic mice.
Reduced autophagy and severe fibrosis were observed in Akita mice and STZ-induced diabetic C57BL/6 mice. Increased autophagy and reduced renal cell fibrosis were found in SCFA-treated Akita diabetic mice and STZ-induced diabetic C57BL/6 mice. Diabetic mice treated with SCFAs had lower HDAC2 expression and more enriched binding of ULK1 promoter sequences to H3K27Ac. Endogenous knockout of HDAC2 caused enhanced autophagy and decreased renal fibrosis in diabetic mice treated with SCFAs.
SCFAs enhanced autophagy of renal tubular cells and attenuated renal fibrosis in diabetic mice through the HDAC2/ULK1 axis.
本研究旨在探讨短链脂肪酸（SCFAs）对糖尿病小鼠模型的影响。
通过 Western blot 和免疫组化（IHC）检测 Akita 小鼠和链脲佐菌素（STZ）诱导的糖尿病 C57BL/6 小鼠的自噬。Western blot、IHC、苏木精和伊红染色、Masson 染色、过碘酸雪夫染色和苦味酸天狼猩红染色用于检测 SCFAs 处理后 Akita 小鼠和 STZ 诱导的糖尿病 C57BL/6 小鼠的自噬和肾功能是否改善。Western blot、IHC 和染色质免疫沉淀用于确定 SCFAs 是否通过组蛋白去乙酰化酶（HDAC2）/UNC-51 样自噬激活激酶 1（ULK1）轴影响糖尿病小鼠。构建了肾脏特异性 HDAC2 敲除的糖尿病小鼠，并进行 IHC、Masson 染色和 Western blot 检测，以检测内源性 HDAC2 的缺失是否有助于改善糖尿病小鼠的自噬和肾纤维化。
在 Akita 小鼠和 STZ 诱导的糖尿病 C57BL/6 小鼠中，观察到自噬减少和严重纤维化。在 SCFA 处理的 Akita 糖尿病小鼠和 STZ 诱导的糖尿病 C57BL/6 小鼠中，自噬增加，肾细胞纤维化减少。用 SCFAs 治疗的糖尿病小鼠的 HDAC2 表达降低，并且 ULK1 启动子序列与 H3K27Ac 的结合更丰富。SCFAs 处理的糖尿病小鼠中，HDAC2 的内源性敲除导致自噬增强，肾纤维化减少。
SCFAs 通过 HDAC2/ULK1 轴增强糖尿病小鼠肾小管细胞的自噬并减轻肾纤维化。
